The findings are published in the August 1, 2014 issue of The Journal of Clinical Investigation.
The receptor or ion channel, called TRPV1, was originally discovered in sensory neurons, where it acts as a sentinel for heat, acidity and spicy chemicals in the environment. “These are all potentially harmful stimuli to cells,” said Eyal Raz, MD, professor of Medicine and senior author of the study. “Thus, TRPV1 was quickly described as a molecular ‘pain receptor.’ This can be considered to be its conventional function, which all takes place in the nervous system.”
But Raz and colleagues have found that TPRV1 is also expressed by epithelial cells of the intestines, where it is activated by epidermal growth factor receptor or EGFR. EGFR is an important driver of cell proliferation in the intestines, whose epithelial lining is replaced approximately every four to six days.
“A basic level of EGFR activity is required to maintain the normal cell turnover in the gut,” said Petrus de Jong, MD, first author of the study. “However, if EGFR signaling is left unrestrained, the risk of sporadic tumor development increases.”
The scientists discovered that TRPV1, once activated by the EGFR, initiates a direct negative feedback on the EGFR, dampening the latter to reduce the risk of unwanted growth and intestinal tumor development. They found that mice genetically modified to be TRPV1-deficient suffered higher-than-normal rates of intestinal tumor growths.
“These results showed us that epithelial TRPV1 normally works as a tumor suppressor in the intestines,” said de Jong. In addition, molecular studies of human colorectal cancer samples recently uncovered multiple mutations in the TRPV1 gene, though Raz noted that currently there is no direct evidence that TRPV1 deficiency is a risk factor for colorectal cancer in humans.
“A direct association between TRPV1 function and human colorectal cancer should be addressed in future clinical studies,” he said.
But if such proves to be the case, the current study suggests one potential remedy might be spicy capsaicin, which acts as an irritant in mammals, generating a burning sensation in contact with tissue. Capsaicin is already broadly used as an analgesic in topical ointments, where its properties as an irritant overwhelm nerves, rendering them unable to report pain for extended periods of time. It’s also the active ingredient in pepper spray.
The researchers fed capsaicin to mice genetically prone to developing multiple tumors in the gastrointestinal tract. The treatment resulted in a reduced tumor burden and extended the lifespans of the mice by more than 30 percent. The treatment was even more effective when combined with celecoxib, a COX-2 non-steroidal anti-inflammatory drug already approved for treating some forms of arthritis and pain.
Co-authors include Petrus R. de Jong, UCSD Department of Medicine and University Medical Center Utrecht, The Netherlands; Naoki Takahashi, UCSD Department of Medicine and Niigata University Graduate School of Medical and Dental Sciences, Japan; Alexandra R. Harris, Jihyung Lee, Samuel Bertin, James Jeffries, Michael Jung, Jen Duong, Amy I. Triano, Jongdae Lee, David S. Herdman, Hui Dong, Lars Eckmann and Maripat Corr, UCSD Department of Medicine; Yaron Niv, Rabin Medical Center and Tel Aviv University, Israel; Koji Taniguchi, UCSD Department of Medicine and Keio University School of Medicine, Japan; Chang-Whan Kim, UCSD Department of Medicine and Catholic University of Korea; Stephanie M Stanford and Nunzio Bottini, La Jolla Institute for Allergy and Immunology.
This research was supported, in part, by the Crohn’s and Colitis Foundation of America, the Prins Bernhard Cultural Foundation, the Scholten-Cordes Foundation, the Dr. Hendrick Muller Vaderlandsch Foundation, the Japan Society for the Promotion of Science, the European Molecular Biology Organization, the Juvenile Diabetes Research Foundation, the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation, the Broad Medical Foundation and the National Institutes of Health (grants AI095623 and DK35108).